Rom J Leg Med [19] 95-100 [2011] DOI: 10.4323/rjlm.2011.95 © 2011 Romanian Society of Legal Medicine

Rapidly fatal necrotizing fasciitis: report of three cases

Karadzić Radovan1*, Goran Ilic1, Aleksandra Antovic1, Lidija Kostić Banovic1, Milic Miroslav1, Dinic Marina2

______Abstract: Necrotizing fasciitis is a rare but life-threatening soft tissue characterized by necrotizing process of the subcutaneous tissues and fascial planes, with resulting skin and systemic toxicity. We describe three fatal cases of clinically undiagnosed necrotizing fasciitis caused by Streptococcus pyogenes. In all cases, the evolution of was fulminant, and all patients were treated with non-steroidal anti-inflammatory drugs. Recently have been reported an association between using of this drugs with an increased incidence of fulminant evolution of necrotizing facciitis. The paper also highlighted the correlation between the histopathologic features of infected tissue with poor acute inflammatory response, and a high concentration of bacteria in infected tissue, which have been confirmed using Gram staining modified by Brown&Bremm. These presented cases emphasize the need for early diagnosis, because prompt clinically recognition prevents unnecessary morbidity and mortality. Key Words: Necrotizing fasciitis, Streptococcus pyogenes, Forensic

ecrotizing fasciitis (NF) is agressive and destructive infection of the subcutaneous Ntissues, associated with substantial mortality and long-term morbidity. It was actually first described by Hippocrates in the 5th century BC as a complication of erysipelas [1]. NF caused by beta-hemolytic streptococci was first described by Meleney in 1924. It has been described under various synonyms, including hospital gangrene, hemolytic or acute streptococcal gangrene, Meleney’s gangrene and Fournier’s gangrene. Wilson first coined the term “necrotizing fasciitis” in 1952. It has been considered as a severe but relatively rare disease [1-3]. In recent years, there has been reported a dramatic increase in the number of NF caused by Streptococcus pyogenes (S. pyogenes) associated with toxic shock syndrome (TSS) [2, 3]. According to medical data from Forensic institute in Nis - Serbia, for 20 years there was no recorded cases of NF, and then in less than a year, we recorded three cases. To the best of our knowledge, there are no previous reported similar cases from Serbia.

Case report In the three cases presented the diagnosis of S. pyogenes NF was based on the antemortem medical data, apperances at postmortem examination, histopathological findings together with definitive bacteriological identification from postmortem cultures from the infected site and blood. Histopathological examination of affected soft tissues and parenchymal organs were conducted using clasic Hematoxilin&Eosin (HE) staining, and histochemistry

1) * Corresponding author: Professor, MD, PhD, Institute of Forensic Medicine, Medical faculty Nis - Serbia; Address: Bulevar Dr Zorana Djindjica 81, 18000 Niš, Serbia; E-mail: [email protected]; Fax: +38118-4233- 776; Tell: +38165-832-40-41 2) MD, PhD, Institute of Microbiology, Medical faculty Nis – Serbia

95 Radovan K et al Rapidly fatal necrotizing fasciitis: report of three cases methods: Van-Gieson for elastic tissue and Gram staining modified by Brown&Bremm, for gram positive bacteria identification in the deparafinized tissue sections. This reaserch on the human was approved by the Internal Ethic Committee of the Medical Faculty University of Nis (Serbia), and conducted at the Institute of Forensic Medicine of this Faculty. Case 1. A 48-year-old previously healthy woman was admitted to hospital, confused, non- febrile, hypotensive and dyspnoeic, five days after pectoral muscle , with gross edema of the arm and chest wall on the right side. The patient was treated with naproxen during 5 days. The initial diagnosis was partial rupture of pectoral major muscle. The physical examination showed a diffuse, erythematous, tender, and nonfluctuant swelling of the arm and chest on the right side with multiple blisters and bullae filled with serosanguinous fluid. Radiologic examination showed no signs of fractures and no gas in the soft tissues, and the needle aspiration of the chest swelling gave about 15 ml of brownish offensive-smelling liquid. The patient was immediately given antibiotics and other supportive treatment, but her general condition rapidly deteriorates and she died soon after admittion. Postmortem examination showed haemorrhagic gangrena of the skin and necrotizing fasciitis of the arm, neck, hip, and most of the chest and abdominal wall on the right side (Figure 1 and 2). An underlying extensive myositis was present also (Figure 3B). The pericardial, pleural and peritoneal cavity contained bloodstained fluid, and pleura, epicard and peritoneum showed evidence of marked petechial haemorrhage. Congestion and diffuse pulmonal tissue bleeding (Figure 3A), and extensive haemorrhage in the adrenal glands was present. Case 2. A 56 year old insulin non-dependent diabetic female patient presented to the hospital with two days history of a tender left-sided chest pain, associated with a swelling of left upper arm. The past medical history wasn’t significant for . The patient was treated with ibuprofen during

Figure 1. The right side of the body of a 48-year-old woman, showing a signs typical of necrotizing fasciitis: diffuse skin haemorrhage with multiple blisters and bullae filled with serosanguinous fluid (case 1).

Figure 3. Internal postmortem examination findings (case 1): Petechial haemorrhage of the pericardium with marked Figure 2. Extensive necrotic, haemorrhagic and bullous skin pleural and pulmonal haemorrhage (3A); an extensive changes: necrotizing fasciitis of the right arm (case 1). haemorrhagic myositis of the chest wall muscles (3B).

96 Romanian Journal of Legal Medicine Vol. XIX, No 2(2011)

3 days. The initial diagnosis was stabil pectoral angina. At the admission, except of the slight edema of left side of the chest wall, there were no other skin changes. Over the next few hours, the patient became hypotensive and dyspnoeic, the skin of the trunk on the left side became red and swollen with haemorrhagic bullae. The body temeperature was normal, and the parenteral supportive therapy was applied. The patient became restless and looked severely ill, and despite all efforts of treatment she died 10 hours after admission. Postmortem examination showed similar features to those in case 1. Necrotizing fasciitis and myositis affected the upper arm, chest wall and lumbal region on the left side (Figure 4). There was haemorrhage of the pleura, pericardium, peritoneum, as well as the pulmonal, renal and adrenal tissue. Case 3. A 57 years old man was admitted to hospital in very hard condition, and febrile for 24 h, five days after injury from a fall. Before admission, the patient was treated with aspirin and diclofenac. The physical examination showed a Figure 4. The left side of the body of a 56-year-old woman, few abrasions on the head and right arm, as showing a dusky skin and haemorrhagic bullae (case 2). well as severe edema and confluent bruising of the arm, shoulder, and upper third of the trunk on the right side. These were tought to be result of the fall before admittion. Radiologic examination revealed no fracture. The patient was febrile, tachicardic and hypotensive. The only treatment given was intravenous saline and sympthomatic terapy. There was a rapid decline in his clinical condition and ensued 3 hours after admission. Postmortem examination showed right-sided necrotizing fasciitis affecting the arm and chest on the right side. The underlying muscles was necrotic, swollen, with large amounth of foul-smelling fluid. The myocardium was pale and flabby and the other internal organs were congested with various degree of hemorrhage. Etiological examination. Sterile specimens, smears and tissue cuts, taken from skin, subcutaneous and muscle tissue, and blood, were cultured for both anaerobic and aerobic organisms. Bacteriological identification confirmed pathogen Streptococcus pyogenes in all cases. Unfortunately, there were no technical requirements for determining the serotypes of these bacteria. . In all cases histopathological examination confirmed the diagnosis of necrotizing fasciitis: of the superfitial fascia and blood vessels thrombosis. Other consistent features include the following: severe subcutaneous necrosis and overlying dermis with slight to moderate inflammatory cells infiltration, and myonecrosis of underlying skeletal muscle (Figure 5). Van-Gieson stained preparations confirmed “melting” of fibrous connective tissue (Figure 6). Using Gram staining modified by Brown&Bremm, a massive invasion of gram positive bacteria were seen in necrotic areas of the skin, subcutaneal tissue, between fat lobules, and in muscle tissue (Figure 7). The internal organs findings include the following: pulmonal microthrombosis and variable degrees of hemorrhage from case to case; myocardial fragmentation and degeneration with some neutrofiles and a variable number of red blood cells in the intestitial tissue; focal and spotty necrosis of liver; extensive haemorrhaging in the renal and adrenal glands tissue.

Discusion Streptococcus pyogenes (group A, beta-haemolytic streptococcus in the Lancefield classification) is one of the most common human pathogens. Invasive group A streptococcal can cause a variety of skin, soft tissue infections and TSS by the action of streptococcal pyrogenic exotoxins [4]. The mortality and morbidity of group A streptococcal necrotizing fasciitis has evolved differently.

97 Radovan K et al Rapidly fatal necrotizing fasciitis: report of three cases

Figure 5. Histopathologic findings of muscle tissue specimen Figure 6. Histopathologic findings of subcutaneal tissue demonstrates myonecrosis and diffuse haemorrhage with specimen demonstrates fragmentation of the collagen fibres relatively poor acute inflammatory cells infiltration. (HE x 20). that are without recognizable vertical stripping. „Melting“ of collagen is evident of very pale colour instead of deep red colour. (Van-Gieson x 300).

In the pre antibiotic era this infection carried a of about 25% when treated with surgery (such as “bear claw” fasciotomies) alone. Mortality due to group A streptococcal NF has not decreased and continued to range from 30% to 70% despite antibiotics, appropriate surgical debridement, and intensive supportive care. This suggests that strains that are more virulent must be responsible [4, 5]. NF has been divided into distinct groups based on bacterial culture results. Type I comprise poly microbial infection (but not including S. pyogenes) that typically involves the trunk and generally results from surgical wound complications. Type II involves group A streptococci, with or without staphylococci. This type of infection more typically affects the extremities. A third type of necrotizing infection is Figure 7. A diffuse presence of gram positive bacteria caused by marine vibrios (gram-negative rods such is (blue) in the subcutaneal fat and muscle tissue (yellow) with Vibrio vulnificus), and the typical portal of entry is a thrombosed blood vessels (yellow) (A); massive bacterial puncture wound or skin abrasion exposed to seawater invasion (blue) of skin tissue (yellow) (B) (Gram staining [3 - 5]. NF may affect patients of all ages, without sex modified by Brown&Bremm; x 20 (A); x 4 (B)). or race predilection. It usually occurs in the perineum, extremities, or abdominal wall, but it can affect any part of the body [4, 6]. Predisposing factors include a history of penetrating or blunt trauma [6], muscle strain [7], burns, childbirth, chickenpox [8], non-steroidal anti-inflammatory drugs (NSAIDs) [9], etc. Most patients who develop NF have pre-existing conditions that result immunosuppression, such as advanced age [1], diabetes mellitus, chronic renal failure, peripheral vascular disease [1, 4]. However, NF also occurs in young, previously healthy individuals who sustained minor trauma to an extremity. In this population, the pathogenic organism is commonly a virulent strain of Streptococcus pyogenes, with the clinical presentation of streptococcal TSS [7]. The clinical signs and symptoms of NF are nonspecific. Most commonly, infection developed within 24 to 72 hours at a site of minor local trauma. Excruciating pain witch usually involves extremities, with or

98 Romanian Journal of Legal Medicine Vol. XIX, No 2(2011) without cutaneous findings, may be the only clue of infection and it is the most common reason for patients to seek medical care [2 - 6]. In the begining, the skin is red-hot, smooth, tense and tender, without sharp demarcation between the involved and normal skin. Early in the course of disease, patients may have an influenza-like syndrome characterized by chills, fever, myalgia, nausea, vomiting, and diarrhoea. As the disease progresses, the skin become dusky, covered with bullae filled with serosanguinous fluid. When the bullous stage is observed, there is already extensive necrotizing fasciitis and myositis and patients usually exhibit haemodynamic disturbances caused by systemic toxicity with evidence of multiorgan failure such as disseminated intravascular coagulation, respiratory failure and septic shock [3-5, 9]. All the cases of NF in this report had a fulminating course with fatal outcome. The is toxic shock with a generalized severe multisystem disorder. There was evidence of trauma in two cases (cases 1 and 3) with spreading of infection away from the primary site and systemic toxic effects. In one case (case 2), subcutaneous and deep muscle tissue was affected without defined bacterial portal of entry. The portal of entry of streptococci cannot be proven in at least half of the cases. Among this patients, hematogenous spread of group A streptococci from a distant site of infection (asymptomatic or symptomatic pharyngitis) probably occurs. The other possibility, which is of course highly conjectural, is that group A streptococci reside in a dormant state in the deep tissue and trauma of various types reactivates their growth [4, 6, 7]. The major findings of reported cases are extensive subcutaneous and muscle tissue destruction. The extent of fascial necrosis was more widespread than changes in the overlying skin. The precise mechanism that resulting in of the superficial fascia and fat is not known. Some investigators believe it is caused by bacterial , including hyaluronidase and , which degrade fascia and fat, respectively [3, 4]. The common histopathologic features of this cases are severe subcutaneous fat necrosis, myonecrosis, thrombosis of blood vessels, abundant bacteria spreading along fascial planes, and relatively few acute inflammatory cells. Pathogenic mechanisms that account for the lack of acute inflammatory response in infected tissue remain to be elucidated. These mechanisms may involve both host and pathogen factors. Infection, local , and reduced host defense mechanisms combine to form a vicious cycle, which is responsible for the initiation and spread of the lesion [4, 10]. Bakleh M. et al. emphasized correlation between the histopathologic features of resected tissue in patients with NF and clinical outcome [11]. According to this research, the mortality rate was higher in cases with poor acute inflammatory response and a high concentration of bacteria in infected tissue. Our conclusion was the same, because histopathological examination showed poor neutrophil response (HE method) and severe presence of bacteria (Gram staining modified by Brown&Bremm) in infected tissue of all three cases. One of the possible reasons for poor inflammatory response is using NSAIDs drugs for pain and . As stated above, all three patients in this report were treated with NSAIDa, which has recently been reported to be associated with an increased incidence of fulminant evolution of NF. Impairment of the host immune response has been proposed as an explanation for this association by augmentination of cytokine production, inhibition of granulocyte adherence, cell activation, and phagocytosis by NSAIDs [3, 9, 10]. We suspect that administration of NSAIDs in patients with skin and soft tissue infections, particularly those caused by Streptococcus pyogenes, delays diagnosis by masking symptoms and signs, allowing a minor infection to develop into a fulminant one.

Conclusion The cases we have described of fulminant streptococcal necrotizing fasciitis reinforce the message that Streptococcus pyogenes can be fatal in a very short period. Diagnosis is often missed because of paucity of symptoms and the unfamiliarity of this pathological entity, not only among clinicians but also for pathologists. For the pathologist is important to be aware of existence of this condition and to perform appropriate dissection with retention of materials for microbiological and histological examination.

99 Radovan K et al Rapidly fatal necrotizing fasciitis: report of three cases

References 1. Hecser L, Croitorescu L, Csiki G, Matei D. Fasciita necrozanta a membrului inferior cu evolutie letala. Rom J Leg Med 2007; 15 (1): 1 – 7 (In Romanian) 2. James DS, Hulewicz B. Rapid death due to group A streptococcal infections: necrotizing fasciitis and acute bacterial myositis. Am J Forensic Med Pathol 1992;13(1):28-32 3. Stevens DL. Invasive streptococcal infections. J Infect Chemother 2001;7:69–80 4. Hasham S, Matteucci P, Stanley PR, Hart NB. Necrotizing fasciitis. BMJ 2005;330:830-833 5. Bisno AL, Stevens DL. Streptococcal infections of skin and soft tissues. N Engl J Med 1996;334: 240-245 6. Nuwayhid ZB, Aronoff DM, Mulla ZD. Blunt trauma as a risk factor for group A streptococcal necrotizing fasciitis. Annals of Epidemiology 2007;17(11):878-881 7. Wojno KS, Werner U. Necrotizing fasciitis: a fatal outcome following minor trauma: case report and literature review. Am J Forensic Med Pathol 1989;10(3):239-241 8. Hidalgo-Carballal A, Suárez-Mier MP. Sudden unexpected death in a child with varicella caused by necrotizing fasciitis and streptococcal toxic shock syndrome. Am J Forensic Med Pathol 2006; 27(1):93-96 9. Stevens DL. Could nonsteroidal antiinflammatory drugs (NSAIDs) enhance the progression of bacterial infections to toxic shock syndrome? Clin Infect Dis 1995;21:977-980 10. Sperry K, Mc Feeley PJ. Medico legal aspects of necrotizing fasciitis of the neck. J Forensic Sci 1987;32(1):273-281 11. Bakleh M., Wold LE, Mandrekar JN, Harmsen WS, Dimashkieh HH, Baddour LM. Correlation of histopathologic findings with clinical outcome in necrotizing fasciitis. Clin Infect Dis 2005;40:410–414

100